2. Morning Report May 20, 2009 Bridger Clarke

3.  Born in Lawrence, Massachusetts, on 4 January 1928.  Dropped out of high school at the age of fourteen and joined the Navy during WWII.  Discharged from the Navy in 1946, he became a professional boxer in upper New York State  Obtained his GED and attended the University of Oklahoma, graduating in 1951.  Eventually attended medical school at UT Galveston and residency at University of Nebraska, completed in 1964.

4.  In 1962, Charles Magnuson, a gastroenterologist at the Omaha VA, asked Lynch to consult on a patient with a strong family history of CRC.  Lynch presumed FAP, but discovered a strong familial predilection for CRC in the absence of multiple polyps.  He presented his findings at a meeting of the American Society of Human Genetics in 1964.

5.  The story goes that his presentation reminded Marjorie Shaw, a medical geneticist at the University of Michigan, of another family with similar characteristics.  In 1966, she and Lynch published their first report of these two families, family N from Nebraska, and family M from Michigan.  Initially called “cancer family syndrome” (CFS), it is now kn0wn as Lynch Syndrome.

6.  Most common of the inherited colon cancer susceptibility syndromes (FAP, JP).  “HNPCC” can be misleading as the disorder predisposes to a variety of other cancers.  The designation of “Lynch Syndrome I and II” is also going out of favor.

7.  Mean age of diagnosis is 47 years old, as opposed to 64 years old in patients without the syndrome.  10% have multiple tumors at the time of diagnosis  Accounts for 2-3% of colorectal cancers and ~2% of uterine cancers.  Approximately 4,000 new cases of Lynch Syndrome each year.

8.  Lifetime risk of colorectal cancer is ~70%  CRCs in Lynch Syndrome evolve from adenomas, but differ from sporadic cancers:  More proximal  Larger  Flatter  More high grade dysplasia and villous histology  The adenoma-carcinoma sequence progresses more rapidly, and new cancers can occur within 2-3 yrs of a negative colonoscopy.

9.  Endometrial cancer is the most common, occurring in up to 70% of women who are gene carriers.  Other sites include:  Ovarian, gastric, small bowel, renal pelvis, ureter, pancreatic, and brain cancers.  Debate about whether prostate and breast cancer are part of Lynch Syndrome.

10.  Caused by a mutation in one of several DNA mismatch repair (MMR) genes (MLH-1, MSH-2, MSH-6).  The MMR system recognizes base-pair mismatches that occur during DNA replication and repairs them.  DNA mismatches commonly occur in repetitive sequences called microsatellites.  Loss of MMR leads to expansion/contraction of microsatellite region, termed ‘microsatellite instability’, and an increased rate of mutation.

11.  Three or more family members with HNPCC-related cancers, one of whom is a first degree relative of the other two  Two successive affected generations  One or more of the HNPCC-related cancers  Diagnosed under age 50 years  FAP has been excluded.

12.  1. CRC in pt <50 years old.  2. Any patient with synchronous/metachronous CRC or HNPCC-associated tumors, regardless of age.  3. CRC with the MSI-H-like histology in a pt <60 yo.  4. CRC in a patient with one or more first-degree relatives with a HNPCC-related tumor diagnosed <50 yo.  5. CRC in a patient with >1 first- or second-degree relatives with HNPCC-related tumors, regardless of age.

13.  Screening recommendations for patients with MMR gene mutations:  Colonoscopy every 1-2 years beginning at age 20, or 10 years earlier than the youngest age of colon cancer diagnosis in the family (whichever comes first).  In families with MSH6 mutations, recommendation is to start at age 30 since the age of onset of colon cancer is later in these families

14.  Endometrial and Ovarian cancer:  Annual screening at age 30, or 5 to 10 years before the earliest age of diagnosis in the family (whichever is earlier). Pelvic exam and endometrial aspirate and transvaginal ultrasound are recommended.  Discussion of prophylactic TAH-BSO at 35 years old.  Annual urinalysis with cytology at age 25-35.  Annual skin exam  Periodic upper endoscopy